1. NCCN NCCN Guidelines IndexNCCN Guidelines Version 1.2012 Breast Cancer Table of ContentsStaging, Discussion NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines)Breast Cancer Version 1.2012NCCN.org NCCN Guidelines for PatientsTM available at www.nccn.com Continue Version 1.2012, 01/20/12 National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN .

2. Printed by manuel garcia on 3/13/2012 12:08:36 PM. For personal use only. Not approved for distribution. Copyright 2012 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN NCCN Guidelines Index NCCN Guidelines Version 1.2012Panel MembersBreast Cancer Table of Contents Breast Cancer Staging, Discussion* Robert W. Carlson, MD/Chair William J. Gradishar, MD Elizabeth C. Reed, MD xStanford Cancer InstituteRobert H. Lurie Comprehensive CancerUNMC Eppley Cancer Center at The Center of Northwestern University Nebraska Medical CenterD. Craig Allred, MDSiteman Cancer Center at Barnes-Jewish Daniel F. Hayes, MD Mary Lou Smith, JD, MBA Hospital and Washington University School of University of Michigan ComprehensiveResearch Advocacy NetworkMedicine Cancer Center Hatem Soliman, MDBenjamin O. Anderson, MD Clifford A. Hudis, MD H. Lee Moffitt Cancer Center & ResearchFred Hutchinson Cancer ResearchMemorial Sloan-Kettering Cancer CenterInstituteCenter/Seattle Cancer Care Alliance Steven Jay Isakoff, MD, PhD George Somlo, MD xHarold J. Burstein, MD, PhD Massachusetts General Cancer Hospital City of Hope Comprehensive Cancer CenterDana-Farber/Brigham and Womens CancerCenter Britt-Marie Ljung, MD Richard l. Theriault, DO UCSF Helen Diller FamilyThe University of Texas MD AndersonStephen B. Edge, MD Comprehensive Cancer Center Cancer CenterRoswell Park Cancer Institute David A. Mankoff, MD, PhD f John H. Ward, MD William B. Farrar, MD Fred Hutchinson Cancer Research Huntsman Cancer Institute at the UniversityThe Ohio State University ComprehensiveCenter/Seattle Cancer Care Alliance of UtahCancer Center - James Cancer Hospital andSolove Research InstituteP. Kelly Marcom, MD Antonio C. Wolff, MD Duke Cancer Institute The Sidney Kimmel Comprehensive CancerAndres Forero, MD Center at Johns Hopkins UniversityUniversity of Alabama at BirminghamIngrid A. Mayer, MD Comprehensive Cancer CenterVanderbilt-Ingram Cancer Center Richard Zellars, MD The Sidney Kimmel Comprehensive CancerSharon Hermes Giordano, MD MPH Beryl McCormick, MD Center at Johns Hopkins UniversityThe University of Texas MD Anderson Cancer Memorial Sloan-Kettering Cancer CenterCenter Lori J. Pierce, MD Lori J. Goldstein, MD University of Michigan ComprehensiveFox Chase Cancer CenterCancer Center Medical Oncology Radiation OncologyContinue Hematology/Oncology f Nuclear medicineNCCN Staff Surgical Oncology x Bone Marrow Transplantation Pathology Patient AdvocacyRashmi Kumar, PhDDorothy A. Shead, MS Reconstructive Surgery* Writing Committee Member Version 1.2012, 01/20/12 National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN . 3. Printed by manuel garcia on 3/13/2012 12:08:36 PM. For personal use only. Not approved for distribution. Copyright 2012 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN NCCN Guidelines Index NCCN Guidelines Version 1.2012 Table of Contents Breast Cancer Table of Contents Breast Cancer Staging, Discussion NCCN Breast Cancer Panel MembersInvasive Breast Cancer (continued) Summary of Guidelines Updates Fertility and Birth Control After Adjuvant Breast Clinical Trials: The NCCN Noninvasive Breast Cancer Cancer (BINV-C) believes that the best management Lobular Carcinoma In Situ (LCIS-1) Surgical Axillary Staging - Stage l, llA ,for any cancer patient is in a clinical Ductal Carcinoma In Situ (DCIS-1) and llB (BINV-D)trial. Participation in clinical trials is Axillary Lymph Node Staging (BINV-E)especially encouraged. Invasive Breast Cancer Margin Status in Infiltrating Carcinoma (BINV-F) To find clinical trials online at NCCN Clinical Stage, Workup (BINV-1) Special Considerations to Breast-Conserving member institutions, click here: Locoregional Treatment of Clinical Stage l, llA, or llB Disease or T3,N1,M0 (BINV-2)Therapy Requiring Radiation Therapy (BINV-G) nccn.org/clinical_trials/physician.html Principles of Breast Reconstruction Following Systemic Adjuvant Treatment (BINV-4)NCCN Categories of Evidence and Mastectomy (BINV-H) Consensus: All recommendations Preoperative Chemotherapy Guideline Principles of Radiation Therapy (BINV-I)are Category 2A unless otherwise = Clinical Stage llA, llB,and IIIA T3,N1,M0 Workup (BINV-10) Adjuvant Endocrine Therapy (BINV-J) specified. = Axillary Evaluation (BINV-11) Adjuvant Chemotherapy (BINV-K)See NCCN Categories of Evidence = Clinical Stage lllA, lllB, IIIA and Stage IV, Definition of Menopause (BINV-L)and Consensus Workup (BINV-14) Principles of Monitoring Metastatic Disease = Preoperative Chemotherapy, Locoregional (BINV-M) Treatment, Adjuvant Treatment (BINV-15) Subsequent Endocrine Therapy (BINV-N) Surveillance/Follow-Up, Recurrence Workup or Preferred Chemotherapy Regimens for Initial Workup for Stage lV Disease (BINV-16) Recurrent or Metastatic Breast Cancer (BINV-O) Treatment of Recurrence/Stage IV DiseaseSpecial Considerations (BINV-17) Phyllodes Tumor (PHYLL-1) Principles of HER2 Testing (BINV-A) Pagets Disease (PAGET-1)NCCN Guidelines for Patients Breast Cancer During Pregnancy (PREG-1) Principles of Dedicated Breast MRI Testing available at www.nccn.com Inflammatory Breast Cancer (IBC-1) (BINV-B) The NCCN Guidelines are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment.Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patients care or treatment. The National Comprehensive Cancer Network (NCCN ) makes no representations orwarranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCNGuidelines are copyrighted by National Comprehensive Cancer Network . All rights reserved. The NCCN Guidelines and the illustrations herein may notbe reproduced in any form without the express written permission of NCCN. 2012. Version 1.2012, 01/20/12 National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN . 4. Printed by manuel garcia on 3/13/2012 12:08:36 PM. For personal use only. Not approved for distribution. Copyright 2012 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN NCCN Guidelines Index NCCN Guidelines Version 1.2012UpdatesBreast Cancer Table of Contents Breast Cancer Staging, Discussion Summary of the changes in the 1.2012 version of the Breast Cancer guidelines from the 2.2011 version include: DISCUSSIONBINV-1 The discussion section has been updated to reflect the recent Modified the workup section: changes in the algorithm. > For clinical stage l and llB, consider additional studies only if directed by signs or symptoms: LCIS-17 Added footnote: Routine systemic staging is not indicated for Removed footnote: The panel endorses the College of American early breast cancer in the absence of symptoms. Pathology Protocol for pathology reporting for all invasive and non-7 Changed pelvic CT to pelvic diagnostic CT invasive carcinomas of the breast.7 Removed ultrasound 7 Changed chest CT to chest diagnostic CT DCIS-1> If clinical stage lllA (T3, N1, M0) consider: Added the following statement to footnote f: Therefore, the7 Changed chest CT to chest diagnostic CT 7 Bone scan or fluoride PET/CT (category 2B) performance of a sentinel lymph node procedure should be7 Added footnote: If FDG PET/ CT are performed and both clearly strongly considered if the patient with apparent pure DCIS is to beindicate bone metastases, bone scan or fluoride PET/CT may not treated with mastectomy or with excision in an anatomic locationbe needed. compromising the performance of a future sentinel lymph node7 Added FDG PET/CT (optional, category 2B) procedure. 7 Modified footnote h: added FDG PET/CT can be performed at the DCIS-2same time as diagnostic CT. Modified footnote m: Some SSRIs like fluoxetine and paroxetine BINV-2 decrease the formation of endoxifen and 4-OH tamoxifen, active 4 positive axillary nodes and 1-3 positive axillary nodes: metabolites of tamoxifen, and may impact its efficacy. Caution is > Changed Consider radiation therapy... to Strongly consider advised about co-administration of these drugs with tamoxifen.radiation therapy... changed from (category 3 to 2B). However citalopram and venlafaxine appear to have minimal impact(Also applies to BINV-3) on tamoxifen metabolism. At this time, based on current data the Modified footnote n: Consider imaging for systemic staging panel recommends against CYP2D6 testing for women being including, diagnostic CT or MRI, bone scan and optional FDG PET/CT considered for tamoxifen therapy. Co-administration of strong (category 2B) inhibitors of CYP2D6 should be used with caution.BINV-3 (also applies to BINV-J, footnote 2) Negative axillary nodes and tumor > 5 cm or margins positive: > Changed Consider radiation therapy... to Strongly consider radiation therapy... changed from (category 3 to 2B). Negative axillary nodes and tumor 5 cm and close margins: > Added Consider to postchemotherapy radiation therapy to chest wall. Continued on the next pageNote: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version 1.2012, 01/20/12 National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN .UPDATES 5. Printed by manuel garcia on 3/13/2012 12:08:36 PM. For personal use only. Not approved for distribution. Copyright 2012 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN NCCN Guidelines Index NCCN Guidelines Version 1.2012UpdatesBreast Cancer Table of Contents Breast Cancer Staging, Discussion BINV-5 Modified footnote oo: It is unclear that women presenting at time of Changed + trastuzumab to with trastuzumab throughout the initial diagnosis with metastatic disease will benefit from the page.performance of palliative local breast surgery and/or radiation BINV-6 therapy. Generally this palliative local therapy should be considered Added adjuvant chemotherapy (category 2B) following pN1mi. only after response to initial systemic therapy. BINV-9 Added a new footnote: A single study (S0226) in women with Changed colloid to mucinous.(also applies to BINV-4) hormone receptor positive breast cancer and no prior chemotherapy, BINV-10biological therapy, or endocrine therapy for metastatic disease Modified the workup section to be consistent with thedemonstrated that the addition of fulvestrant to anastrozole resulted changes on BINV-1. in prolongation of time to progression (Hazard rate for recurrence BINV-120.80; 95% CI 0.68 - 0.94; stratified log-rank p=0.007) and improvement Added a header for Response with footnote dd.in overall survival (hazard rate 0.81; 95% CI 0.65- 1.00; stratified log- Added footnote dd: The accurate assessment of in-breast tumor orrank p = 0.049). Subset analysis suggested that patients without prior regional lymph node response to preoperative chemotherapy is adjuvant tamoxifen and more than 10 years since diagnosis difficult, and should include physical examination and performance experienced the greatest benefit. A study of similar design (FACT) of imaging studies that were abnormal at the time of initial tumor demonstrated no advantage in time to progression with the addition staging.of fulvestrant to anastrozole (Hazard rate 0.99; 95% CI 0.81-1.20; BINV-14p=0.91). Modified the workup section to be consistent with theBINV-19, -20, -21 changes on BINV-1. Added a link to Principles of Monitoring of Metastatic Disease BINV-15(BINV-M). Following response, added strongly consider internal mammary BINV-A nodes if not clinically involved and changed (category 3) to Replaced fluorescence in situ hybridization (FISH) with in situ (category 2B)hybridization (ISH) throughout the page. BINV-16BINV-C Removed Consider from Determination of ER/PR/HER2 status in Modified bullet: All premenopausal patients should be informed the workup of metastatic disease. about the potential impact of chemotherapy on fertility and asked BINV-18about their desire for potential future pregnancies. Patients who may No prior endocrine therapy within 1 y: desire future pregnancies should be referred to fertility specialists > Removed or antiestrogen. before chemotherapy. > Premenopausal, added or selective estrogen receptor BINV-D modulators. This page has been reformatted. > Postmenopausal, added or selective estrogen receptor Added a branch for FNA or core biopsy positive - axillary dissection modulators or selective estrogen receptor down-regulator level l/ll.Continued on the next pageNote: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version 1.2012, 01/20/12 National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN .UPDATES 6. Printed by manuel garcia on 3/13/2012 12:08:36 PM. For personal use only. Not approved for distribution. Copyright 2012 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN NCCN Guidelines Index NCCN Guidelines Version 1.2012UpdatesBreast Cancer Table of Contents Breast Cancer Staging, Discussion BINV-DBINV-K The following information was removed from a footnote and placed Moved AC (doxorubicin/cyclophosphamide) to Other Adjuvant in the algorithm: Regimens. > Meets ALL of the following criteria: Changed Neoadjuvant to Neoadjuvant only. 7 T1 or T2 tumorBINV-M 7 1 or 2 positive SLNs Principles of Monitoring Metastatic Disease - this page is new to 7 Breast conserving therapy the guideline. 7 Whole breast RT planned BINV-N 7 No neoadjuvant chemotherapy A single study (BOLERO-2) in women with hormone receptor Following sentinel node negative inserted consider no further positive, her-2 negative metastatic breast cancer and prior therapy surgery (category 1). with a non-steroidal aromatase inhibitor demonstrated BINV-G improvement in time to progression with the addition of Modified last bullet: Women with a known or suspected genetic everolimus (an mTOR inhibitor) to exemestane (Hazard rate 0.44; predisposition to breast cancer. 95% CI 0.36-0.53; log-rank P = Premenopausal:using the mTOR inhibitor temsirolimus in combination with 7 Changed tamoxifen for 2-3 y to 5y (category 1) followed byendocrine therapy did not demonstrate any improvement inaromatase inhibitor for 5y or no further endocrine therapy.outcome. Consider the addition everolimus to exemestane in > Postmenopausal: women who fulfill the eligibility criteria of BOLERO-2. 7 Added aromastase inhibitor for 2-3 y (category 1) followed bytamoxifen to complete 5 y (category 1). PAGETS-2 7 Tamoxifen for 2-3 y followed by aromatase inhibitor to complete Modified last node, appropriate systemic adjuvant therapy per5y (category 1) changed or longer to or up to 5 y of an DCIS or Invasive Breast Cancer Guidelines.aromastase inhibitor (category 2B). Deleted the following footnote: This specific patient subset was not PREG-1 included in the trials of aromatase inhibitors given sequentially with Modified footnote c: There are insufficient safety data to adjuvant tamoxifen. Some women who appear to become recommend general use of taxanes during pregnancy. Use of postmenopausal on tamoxifen therapy have resumption of ovarianpaclitaxel weekly administration after the first trimester acceptable function after discontinuation of tamoxifen and initiation of anif clinically indicated by disease status. The use of trastuzumab is aromatase inhibitor. Therefore, serial monitoring of plasma estradiol contraindicated during pregnancy. and FSH levels is encouraged in this clinical setting. Should ovarian function resume, the aromatase inhibitor should be discontinued and tamoxifen resumed. See Definition of Menopause (BINV-L). Continued on the next pageNote: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version 1.2012, 01/20/12 National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN .UPDATES 7. Printed by manuel garcia on 3/13/2012 12:08:36 PM. For personal use only. Not approved for distribution. Copyright 2012 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN NCCN Guidelines Index NCCN Guidelines Version 1.2012UpdatesBreast Cancer Table of Contents Breast Cancer Staging, Discussion IBC-1 Modified the workup section. > Changed chest CT to chest diagnostic CT > Bone scan or fluoride PET/CT (category 2B) > Added FDG PET/CT (category 2B) > Modified footnote f: FDG PET/CT can be performed at the same time as diagnostic CT. The use of PET or PET/CT scanning is not indicated in the staging of clinical stage I, II, or operable III breast cancer. FDG PET/CT is most helpful in situations where standard staging studies are equivocal or suspicious, especially in the setting of locally advanced or metastatic disease. FDG PET/CT may also be helpful in identifying unsuspected regional nodal disease and/or distant metastases in LABC when used in addition to standard staging studies. Added footnote: The panel endorses the College of American Pathologists Protocol for pathology reporting for all invasive and non-invasive carcinomas of the breast. Added footnote: See Principles of HER2 Testing (BINV-A). Added footnote: See Neoadjuvant/Adjuvant Chemotherapy (BINV-K).Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version 1.2012, 01/20/12 National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN .UPDATES 8. Printed by manuel garcia on 3/13/2012 12:08:36 PM. For personal use only. Not approved for distribution. Copyright 2012 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN NCCN Guidelines Index NCCN Guidelines Version 1.2012 Breast Cancer Table of Contents Staging, Discussion Lobular Carcinoma in Situ DIAGNOSIS WORKUP RISK REDUCTIONSURVEILLANCE Biopsy was core PerformDuctal carcinomaManage per needle biopsy surgical in situ (DCIS) or appropriate (less than surgical excision invasive cancer NCCN Guideline biopsy) a,b Lobular History and carcinoma inphysical situ (LCIS) Diagnostic identified on bilateral breast biopsy mammogram Surveillance as per Stage 0 Pathology NCCN Breast Tis, N0, M0 reviewCancer RiskCounseling regarding LCIS without risk reduction, seeReduction Initial biopsy wasNCCN Breast Cancer Guidelines surgical biopsy a,b other cancerRisk Reduction NCCN BreastGuidelines)Cancer Screening and Diagnosis Guidelines a LCISis present on initial biopsy (needle or surgical) or on final excision with or without other proliferative changes (atypical ductal or lobular hyperplasia). b Some variants of LCIS (pleomorphic LCIS) may have a similar biological behavior to that of DCIS. Clinicians may consider complete excision with negative margins for pleomorphic LCIS, but outcome data regarding the efficacy of surgical excision to negative margins and/or radiotherapy are lacking.Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version 1.2012, 01/20/12 National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN . LCIS-1 9. Printed by manuel garcia on 3/13/2012 12:08:36 PM. For personal use only. Not approved for distribution. Copyright 2012 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN NCCN Guidelines Index NCCN Guidelines Version 1.2012 Breast Cancer Table of Contents Ductal Carcinoma in SituStaging, Discussion DIAGNOSIS WORKUPPRIMARY TREATMENT Lumpectomy d,e without lymph node History and physical examsurgery f + whole breast radiation Diagnostic bilateral mammogram therapyg,h,i,j,k (category 1) Ductal carcinoma Pathology review b or Total mastectomy with or withoutSee in situ (DCIS) Determination of tumor estrogenPostsurgical Stage 0receptor (ER) status sentinel node biopsyf,i reconstruction l Treatment Tis, N0, M0 a Genetic counseling if patient is highor (DCIS-2) Lumpectomy d,e without lymph noderisk for hereditary breast cancer c surgeryf without radiation therapyg,h,j,k (category 2B) a SeeNCCN Breast Cancer Screening and Diagnosis Guidelines. b The panel endorses the College of American Pathologists Protocol for pathology reporting for all invasive and non-invasive carcinomas of the breast.http://www.cap.org. c See NCCN Genetic/Familial High-Risk Assessment: Breast and Ovarian Guidelines. d Re-resection(s) may be performed in an effort to obtain negative margins in patients desiring breast conserving therapy. Patients not amenable to margin-freelumpectomy should have total mastectomy. e See Margin Status in DCIS (DCIS-A). f Complete axillary lymph node dissection should not be performed in the absence of evidence of invasive cancer or proven metastatic disease in women with apparentpure DCIS. However, a small proportion of patients with apparent pure DCIS will be found to have invasive cancer at the time of their definitive surgical procedure.Therefore, the performance of a sentinel lymph node procedure should be strongly considered if the patient with apparent pure DCIS is to be treated with mastectomyor with excision in an anatomic location compromising the performance of a future sentinel lymph node procedure. g See Principles of Radiation Therapy (BINV-I). h Complete resection should be documented by analysis of margins and specimen radiography. Post-excision mammography should also be performed wheneveruncertainty about adequacy of excision remains. i Patients found to have invasive disease at total mastectomy or re-excision should be managed as stage l or stage ll disease, including lymph node staging. j See Special Considerations to Breast-Conserving Therapy (BINV-G). k Whole-breast radiation therapy following lumpectomy reduces recurrence rates in DCIS by about 50%. Approximately half of the recurrences are invasive and half areDCIS. A number of factors determine that local recurrence risk: palpable mass, larger size, higher grade, close or involved margins, and age under 50 years. If thepatient and physician view the individual risk as low, some patients may be treated by excision alone. All data evaluating the three local treatments show nodifferences in patient survival. l See Principles of Breast Reconstruction Following Surgery (BINV-H).Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version 1.2012, 01/20/12 National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN . DCIS-1 10. Printed by manuel garcia on 3/13/2012 12:08:36 PM. For personal use only. Not approved for distribution. Copyright 2012 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN NCCN Guidelines Index NCCN Guidelines Version 1.2012 Breast Cancer Table of Contents Staging, Discussion Ductal Carcinoma in Situ DCIS POSTSURGICAL TREATMENT SURVEILLANCE/FOLLOW-UP Risk reduction therapy for ipsilateral breast following breast conserving surgery: Consider tamoxifen m for 5 years for: Patients treated with breast-conserving therapy Interval history and physical exam every 6-12 mo for (lumpectomy) and radiation therapy n (category 1),5 y, then annually especially for those with ER-positive DCIS. The benefit of Mammogram every 12 mo (and 6-12 mo postradiation tamoxifen for ER-negative DCIS is uncertain therapy if breast conserved [category 2B]) Patients treated with excision alonen If treated with tamoxifen, monitor per NCCN Breast Cancer Risk Reduction Guidelines Risk reduction therapy for contralateral breast: Counseling regarding risk reduction m See also NCCN Breast Cancer Risk Reduction Guidelines m Some SSRIs like fluoxetine and paroxetine decrease the formation of endoxifen and 4-OH tamoxifen, active metabolites of tamoxifen, and may impact efficacy. Caution is advised about co-administration of these drugs with tamoxifen. However, citalopram and venlafaxine appear to have minimal impact on tamoxifen metabolism. At this time, based on current data the panel recommends against CYP2D6 testing for women being considered for tamoxifen therapy. Co-administration of strong inhibitors of CYP2D6 should be used with caution. n Available data suggest tamoxifen provides risk reduction in the ipsilateral breast treated with breast conservation and in the contralateral breast in patients with mastectomy or breast conservation with ER-positive primary tumors. Since a survival advantage has not been demonstrated, individual consideration of risks and benefits is important (See also NCCN Breast Cancer Risk Reduction Guidelines).Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version 1.2012, 01/20/12 National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN . DCIS-2 11. Printed by manuel garcia on 3/13/2012 12:08:36 PM. For personal use only. Not approved for distribution. Copyright 2012 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN NCCN Guidelines Index NCCN Guidelines Version 1.2012 Breast Cancer Table of Contents Staging, Discussion Ductal Carcinoma in Situ MARGIN STATUS IN DCIS Substantial controversy exists regarding the definition of a negative pathologic margin in DCIS. Controversy arises out of the heterogeneity of the disease, difficulties in distinguishing the spectrum of hyperplastic conditions, anatomic considerations of the location of the margin, and inadequate prospective data on prognostic factors in DCIS. Margins greater than 10 mm are widely accepted as negative (but may be excessive and may lead to a less optimal cosmetic outcome). Margins less than 1 mm are considered inadequate. With pathologic margins between 1-10 mm, wider margins are generally associated with lower local recurrence rates. However, close surgical margins ( 5 cm and supraclavicular nodes. Strongly consider radiationBINV-4 stagingi,j (category 1)or therapy o to internal mammary nodes (category 2B) reconstructionmmargins positiveNegative axillary nodesand tumor 5 cm andConsider postchemotherapy radiation therapy o to chest wallclose margins (< 1 mm)Negative axillary nodesand tumor 5 cm andNo radiation therapymargins 1 mm i SeeSurgical Axillary Staging (BINV-D). j See AxillaryLymph Node Staging (BINV-E) and Margin Status in Infiltrating Carcinoma (BINV-F). m See Principles of Breast Reconstruction Following Surgery (BINV-H). n Consider imaging for systemic staging, including diagnostic CT or MRI, bone scan, and optional FDG PET/CT (category 2B) (See BINV-1). o See Principles of Radiation Therapy (BINV-I). p Radiation therapy should be given to the internal mammary lymph nodes that are clinically or pathologically positive, otherwise the treatment to the internal mammary nodes is at the discretion of the treating radiation oncologist. CT treatment planning should be utilized in all cases where radiation therapy is delivered to the internal mammary lymph nodes..Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version 1.2012, 01/20/12 National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN . BINV-3 15. Printed by manuel garcia on 3/13/2012 12:08:36 PM. For personal use only. Not approved for distribution. Copyright 2012 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN NCCN Guidelines Index NCCN Guidelines Version 1.2012 Breast Cancer Table of Contents Staging, DiscussionInvasive Breast Cancer HISTOLOGY HORMONE HER2 STATUS SYSTEMIC ADJUVANT TREATMENT RECEPTOR STATUS HER2 positive b See Systemic Adjuvant Treatment - Hormone Receptor Positive - HER2 Positive Disease (BINV-5) ER-positive and/or PR positive See Systemic Adjuvant Treatment - Hormone HER2 negative b Receptor Positive - HER2 Negative Disease (BINV-6) Ductal s Lobular Mixed HER2 positive b See Systemic Adjuvant Treatment - Hormone Metaplastic Receptor Negative - HER2 Positive Disease (BINV-7) ER-negative and PR-negative HER2 negative b See Systemic Adjuvant Treatment - Hormone Receptor Negative - HER2 Negative Disease (BINV-8) ER-positive and/or PR positive Tubular See Systemic Adjuvant Treatment - Favorable Histologies (BINV-9) Mucinous ER-negative and PR-negativeb SeePrinciples of HER2 Testing (BINV-A).s This includes medullary and micropapillary subtypes.Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version 1.2012, 01/20/12 National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN . BINV-4 16. Printed by manuel garcia on 3/13/2012 12:08:36 PM. For personal use only. Not approved for distribution. Copyright 2012 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN NCCN Guidelines Index NCCN Guidelines Version 1.2012 Breast Cancer Table of Contents Staging, DiscussionInvasive Breast Cancer SYSTEMIC ADJUVANT TREATMENT - HORMONE RECEPTOR POSITIVE - HER2 POSITIVE DISEASE b Tumor 0.5 cm orpN0Consider adjuvant endocrine therapy Microinvasive Adjuvant endocrine therapypN1mi adjuvant chemotherapy u,v,w with trastuzumab xpT1, pT2, or pT3;and pN0 or pN1mi Adjuvant endocrine therapy( 2 mm axillary Tumor 0.6-1.0 cm adjuvant chemotherapy u,v,w Histology: t node metastasis) with trastuzumab x Ductal Lobular Adjuvant endocrine therapy Mixed Tumor > 1 cm+ adjuvant chemotherapy Metaplastic with trastuzumab (category 1) u,v,wNode positive (one or more Adjuvant endocrine therapymetastases > 2 mm to one or more + adjuvant chemotherapyipsilateral axillary lymph nodes)with trastuzumab (category 1) u,v,wSee Follow-Up (BINV-16) See Adjuvant Endocrine Therapy (BINV-J) and Adjuvant Chemotherapy (BINV-K) b SeePrinciples of HER2 Testing (BINV-A). t Mixed lobular and ductal carcinoma as well as metaplastic carcinoma should be graded based on the ductal component and treated based on this grading. The metaplastic or mixed component does not alter prognosis. uEvidence supports that the magnitude of benefit from surgical or radiation ovarian ablation in premenopausal women with hormone-receptor-positive breast cancer is similar to that achieved with CMF alone. Early evidence suggests similar benefits from ovarian suppression (ie, LHRH agonist) as from ovarian ablation. The combination of ovarian ablation/suppression plus endocrine therapy may be superior to suppression alone. The benefit of ovarian ablation/suppression in premenopausal women who have received adjuvant chemotherapy is uncertain. v Chemotherapy and endocrine therapy used as adjuvant therapy should be given sequentially with endocrine therapy following chemotherapy. The benefits of chemotherapy and of endocrine therapy are additive. However, the absolute benefit from chemotherapy may be small. The decision to add chemotherapy to endocrine therapy should be individualized, especially in those with a favorable prognosis where the incremental benefit of chemotherapy may be smaller. Available data suggest that sequential or concurrent endocrine therapy with radiation therapy is acceptable. w There are limited data to make chemotherapy recommendations for those over 70 y old. Treatment should be individualized with consideration of comorbid conditions . x The prognosis of patients with T1a and T1b tumors that are node negative is generally favorable even when HER2 is amplified or over-expressed. This is a population of breast cancer patients that was not studied in the available randomized trials. The decision for use of trastuzumab therapy in this cohort of patients must balance the known toxicities of trastuzumab, such as cardiac toxicity, and the uncertain, absolute benefits that may exist with trastuzumab therapy.Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version 1.2012, 01/20/12 National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN . BINV-5 17. Printed by manuel garcia on 3/13/2012 12:08:36 PM. For personal use only. Not approved for distribution. Copyright 2012 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN NCCN Guidelines Index NCCN Guidelines Version 1.2012 Breast Cancer Table of Contents Staging, DiscussionInvasive Breast Cancer SYSTEMIC ADJUVANT TREATMENT - HORMONE RECEPTOR POSITIVE - HER2 NEGATIVE DISEASE b pN0 Consider adjuvant endocrine therapy (category 2B) Tumor 0.5 cm orAdjuvant endocrine therapy u (category 2B) Microinvasive pN1mi adjuvant chemotherapy (category 2B) Adjuvant endocrine therapy upT1, pT2, or pT3;Not done adjuvant chemotherapy wand pN0 or pN1mi (category 1)( 2 mm axillarynode metastasis)Low recurrence Adjuvant endocrinescore (< 18) therapy u (category 2B)Histology: t Consider 21-gene Tumor > 0.5 cm Ductal RT-PCR assay Intermediate Adjuvant endocrine therapy Lobular recurrence Mixedadjuvant chemotherapy u,v,wscore (18-30)(category 2B) Metaplastic Adjuvant endocrine therapy +High recurrenceNode positive (one or moreAdjuvant endocrine therapy adjuvant chemotherapy u,v,w+ adjuvant chemotherapy score ( 31) (category 2B)metastases > 2 mm to one or moreipsilateral axillary lymph nodes) (category 1)See Adjuvant Endocrine Therapy (BINV-J) and Adjuvant Chemotherapy (BINV-K) b SeePrinciples of HER2 Testing (BINV-A). t Mixedlobular and ductal carcinoma as well as metaplastic carcinoma should be graded based on the ductal component and treated based on this grading. The metaplastic or mixed component does not alter prognosis. u Evidence supports that the magnitude of benefit from surgical or radiation ovarian ablation in premenopausal women with hormone-receptor-positive breast cancer is similar to that achieved with CMF alone. Early evidence suggests similar benefits from ovarian suppression (ie, LHRH agonist) as from ovarian ablation. The combination of ovarian ablation/suppression plus endocrine therapy may be superior to suppression alone. The benefit of ovarian ablation/suppression in premenopausal women who have received adjuvant chemotherapy is uncertain. v Chemotherapy and endocrine therapy used as adjuvant therapy should be given sequentially with endocrine therapy following chemotherapy. The benefits of chemotherapy and of endocrine therapy are additive. However, the absolute benefit from chemotherapy may be small. The decision to add chemotherapy to endocrine that therapy should be individualized, especially in those with a favorable prognosis where the incremental benefit of chemotherapy may be smaller. Available data suggest sequential or concurrent endocrine therapy with radiation therapy is acceptable. w There are limited data to make chemotherapy recommendations for those over 70 y old. Treatment should be individualized with consideration of comorbid conditions .Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version 1.2012, 01/20/12 National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN . BINV-6 18. Printed by manuel garcia on 3/13/2012 12:08:36 PM. For personal use only. Not approved for distribution. Copyright 2012 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN NCCN Guidelines Index NCCN Guidelines Version 1.2012 Breast Cancer Table of Contents Staging, DiscussionInvasive Breast Cancer SYSTEMIC ADJUVANT TREATMENT - HORMONE RECEPTOR NEGATIVE - HER2 POSITIVE DISEASE bpN0 No adjuvant therapy Tumor 0.5 cm or Microinvasive Consider adjuvant chemotherapy wpN1miwith trastuzumab xpT1, pT2, or pT3; and pN0or pN1mi ( 2 mm axillary Tumor 0.6-1.0 cmConsider adjuvant chemotherapy wnode metastasis)with trastuzumab xTumor > 1 cmAdjuvant chemotherapy w (category 1)Histology: twith trastuzumab (category 1) Ductal Lobular Mixed MetaplasticNode positive (one or moreAdjuvant chemotherapy wmetastases > 2 mm to one or morewith trastuzumab (category 1)ipsilateral axillary lymph nodes)See Follow-Up (BINV-16) See Adjuvant Chemotherapy (BINV-K) b See Principles of HER2 Testing (BINV-A). t Mixed lobular and ductal carcinoma as well as metaplastic carcinoma should be graded based on the ductal component and treated based on this grading. The metaplastic or mixed component does not alter prognosis. w There are limited data to make chemotherapy recommendations for those over 70 y old. Treatment should be individualized with consideration of comorbid conditions. x The prognosis of patients with T1a and T1b tumors that are node negative is generally favorable even when HER2 is amplified or over expressed. This is a population of breast cancer patients that was not studied in the available randomized trials. The decision for use of trastuzumab therapy in this cohort of patients must balance the known toxicities of trastuzumab, such as cardiac toxicity, and the uncertain, absolute benefits that may exist with trastuzumab therapy.Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version 1.2012, 01/20/12 National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN .BINV-7 19. Printed by manuel garcia on 3/13/2012 12:08:36 PM. For personal use only. Not approved for distribution. Copyright 2012 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN NCCN Guidelines Index NCCN Guidelines Version 1.2012 Breast Cancer Table of Contents Staging, DiscussionInvasive Breast Cancer SYSTEMIC ADJUVANT TREATMENT - HORMONE RECEPTOR NEGATIVE - HER2 NEGATIVE DISEASE b pN0 No adjuvant therapy Tumor 0.5 cm or Microinvasive pN1mi Consider adjuvant chemotherapy w pT1, pT2, or pT3; and pN0 or pN1mi ( 2 mm axillary Tumor 0.6-1.0 cmConsider adjuvant chemotherapy w node metastasis) Tumor > 1 cm Adjuvant chemotherapy w (category 1) Histology: t Ductal Lobular Mixed Metaplastic Node positive (one or more metastases > 2 mm to one or more Adjuvant chemotherapy w (category 1) ipsilateral axillary lymph nodes)See Follow-Up (BINV-16)See Adjuvant Chemotherapy (BINV-K) b See Principles of HER2 Testing (BINV-A). t Mixedlobular and ductal carcinoma as well as metaplastic carcinoma should be graded based on the ductal component and treated based on this grading. Themetaplastic or mixed component does not alter prognosis. w There are limited data to make chemotherapy recommendations for those over 70 y old. Treatment should be individualized with consideration of comorbid conditions.Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version 1.2012, 01/20/12 National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN .BINV-8 20. Printed by manuel garcia on 3/13/2012 12:08:36 PM. For personal use only. Not approved for distribution. Copyright 2012 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN NCCN Guidelines Index NCCN Guidelines Version 1.2012 Breast Cancer Table of Contents Staging, DiscussionInvasive Breast Cancer SYSTEMIC ADJUVANT TREATMENT - FAVORABLE HISTOLOGIESpT1, pT2, or pT3; < 1 cmNo adjuvant therapy yand pN0 or pN1miConsider adjuvant( 2 mm axillary1-2.9 cmendocrine therapyu,w ER-positivenode metastasis) and/or 3 cmAdjuvant endocrine therapy u,w PR-positiveNode positive (one or moremetastasis > 2 mm to one or moreAdjuvant endocrine therapy ipsilateral axillary lymph nodes) adjuvant chemotherapy u,wHistology: Tubular Mucinous ER-positive and/or Follow appropriate pathway above PR-positive ER-negativeRepeat determination of andtumor estrogen/progesterone PR-negativereceptor (ER/PR) status ER-negative Treat as usual breast cancer histology and (See BINV-7 and BINV-8) PR-negativeSee Adjuvant Endocrine Therapy (BINV-J) and Adjuvant Chemotherapy (BINV-K) u Evidencesupports that the magnitude of benefit from surgical or radiation ovarian ablation in premenopausal women with hormone-receptor-positive breast cancer issimilar to that achieved with CMF alone. Early evidence suggests similar benefits from ovarian suppression (ie, LHRH agonist or antagonist) as from ovarian ablation.The combination of ovarian ablation/suppression plus endocrine therapy may be superior to suppression alone. The benefit of ovarian ablation/suppression inpremenopausal women who have received adjuvant chemotherapy is uncertain. w There are limited data to make chemotherapy recommendations for those over 70 y old. Treatment should be individualized with consideration of comorbid conditions. y If ER-positive, consider endocrine therapy for risk reduction and to diminish the small risk of disease recurrence.Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version 1.2012, 01/20/12 National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN . BINV-9 21. Printed by manuel garcia on 3/13/2012 12:08:36 PM. For personal use only. Not approved for distribution. Copyright 2012 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN NCCN Guidelines Index NCCN Guidelines Version 1.2012 Breast Cancer Table of Contents Staging, DiscussionInvasive Breast Cancer Preoperative Chemotherapy GuidelineCLINICAL STAGEWORKUP History and physical exam CBC, plateletsStage IIA Liver function tests and alkaline phosphatase T2, N0, M0 Diagnostic bilateral mammogram, ultrasound as necessary Pathology review aStage IIB Determination of tumor estrogen/progesterone receptor (ER/PR) status and HER2 statusb T2, N1, M0 Genetic counseling if patient is high risk for hereditary breast cancer c T3, N0, M0 Breast M RId (optional) Consider fertility counseling if indicated e See PreoperativeStage lllA Chemotherapy T3, N1, M0 If clinical stage lllA (T3, N1, M0)consider: f Axillary Chest diagnostic CTEvaluationand Abdominal pelvic diagnostic CT or MRI(BINV-11) Bone scan or fluoride PET/CT g (category 2B)Fulfills criteria FDG PET/CT h (optional, category 2B)for breastconservingOptional studies as directed by signs or symptoms: fsurgery Bone scan indicated if localized bone pain or elevated alkaline phosphataseexcept for Abdominal pelvic diagnostic CT or MRI indicated if elevated alkaline phosphatase, abnormal livertumor sizefunction tests, abdominal symptoms, or abnormal physical examination of the abdomen or pelvis Chest diagnostic CT if pulmonary symptoms present f Routinesystemic staging is not indicated for early breast cancer in the absence of symptoms. g If FDG PET/CT are performed and both clearly indicate bone metastases, bonea The panel endorses the College of American Pathologists Protocol for pathology scan or fluoride PET/CT may not be needed.reporting for all invasive and non-invasive carcinomas of the breast.h FDG PET/CT can be performed at the same time as diagnostic CT. The use of PEThttp://www.cap.org.or PET/CT scanning is not indicated in the staging of clinical stage I, II, or operableb See Principles of HER2 Testing (BINV-A). III breast cancer. FDG PET/CT is most helpful in situations where standard stagingc See NCCN Genetics/Familial High-Risk Assessment: Breast and Ovarian studies are equivocal or suspicious, especially in the setting of locally advanced orGuidelines.metastatic disease. FDG PET/CT may also be helpful in identifying unsuspectedd See Principles of Dedicated Breast MRI Testing (BINV-B). regional nodal disease and/or distant metastases in LABC when used in addition toe See Fertility and Birth Control After Adjuvant Breast Cancer Treatment (BINV-C). standard staging studies.Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version 1.2012, 01/20/12 National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN . BINV-10 22. Printed by manuel garcia on 3/13/2012 12:08:36 PM. For personal use only. Not approved for distribution. Copyright 2012 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN NCCN Guidelines Index NCCN Guidelines Version 1.2012 Breast Cancer Table of Contents Staging, DiscussionInvasive Breast Cancer Preoperative Chemotherapy Axillary Evaluation Clinically negative axillary lymph node(s), consider sentinel lymph node procedure i Consider axillary ultrasound; if clinically positive see belowSee Preoperative Core biopsy of breast tumor, Chemotherapy - Desires breastlocalization of tumor bed for preservation Primary Treatment future surgical management (BINV-12) Clinically positive axillary lymph node(s), consider core biopsy or FNA; or consider sentinel lymph node procedure if FNA or core biopsy negative Does not desireSee Locoregional Treatment of Clinical Stage I, IlA, or IlB Disease breast preservationor T3, N1, M0 (BINV-3) i See Surgical Axillary Staging (BINV-D).Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version 1.2012, 01/20/12 National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN . BINV-11 23. Printed by manuel garcia on 3/13/2012 12:08:36 PM. For personal use only. Not approved for distribution. Copyright 2012 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN NCCN Guidelines Index NCCN Guidelines Version 1.2012 Breast Cancer Table of Contents Staging, DiscussionInvasive Breast Cancer Preoperative Chemotherapy Guideline PRIMARY TREATMENTRESPONSE dd No response after3-4 cyclesNo response after or3-4 cyclesProgressive diseaseSeeor MastectomyProgressive disease(BINV-13)ConsiderPartial response,alternativelumpectomy not possiblechemotherapy Preoperative chemotherapy z,aa,bb (endocrine therapy alone may bePartial response, considered for receptor positive lumpectomy notComplete response or See disease in postmenopausal patients) cc possiblepartial response,Lumpectomylumpectomy possible(BINV-13)Partial response,lumpectomy possibleSeeor Lumpectomy (BINV-13)Complete response z A number of combination and single-agent chemotherapy regimens have activity in the preoperative setting. In general, those chemotherapy regimens recommended in the adjuvant setting (See BINV-K) may be considered in the preoperative setting. If treated with endocrine therapy, an aromatase inhibitor is preferred for postmenopausal women. aa Patients with HER2-positive tumors should be treated with preoperative chemotherapy incorporating trastuzumab for at least 9 weeks of preoperative therapy (See BINV-K). bb Administration of all chemotherapy prior to surgery is preferred. cc Definition of Menopause (See BINV-L). dd The accurate assessment of in-breast tumor or regional lymph node response to preoperative chemotherapy is difficult, and should include physical examination and performance of imaging studies that were abnormal at the time of initial tumor staging.Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version 1.2012, 01/20/12 National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN . BINV-12 24. Printed by manuel garcia on 3/13/2012 12:08:36 PM. For personal use only. Not approved for distribution. Copyright 2012 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN NCCN Guidelines Index NCCN Guidelines Version 1.2012 Breast Cancer Table of Contents Staging, DiscussionInvasive Breast Cancer Preoperative Chemotherapy Guideline LOCAL TREATMENTADJUVANT TREATMENT Adjuvant radiation therapy o post-mastectomy is Mastectomy and based on prechemotherapy tumor characteristics surgical axillaryas per BINV-3and staging ee Endocrine therapy if ER-positive and/or PR- reconstruction. If Consider additional positive v (category 1) sentinel lymph nodechemotherapy in the Complete up to one year of trastuzumab therapy if biopsy performed context of a clinical trial HER2-positive (category 1). May be administered prechemotherapy andconcurrent with radiation therapyo and with negative findings, may endocrine therapy if indicated.See Adjuvant Endocrine Therapy (BINV-J) omit axillary lymph node stagingSee Surveillance/Follow-up (BINV-16) Adjuvant radiation therapy o post-lumpectomybased on prechemotherapy tumor characteristics Lumpectomy withas per BINV-2 surgical axillaryand staging. ee If sentinel Endocrine therapy if ER-positive and/or PR- lymph node biopsyConsider additional positive v (category 1)chemotherapy in the Complete up to one year of trastuzumab therapy if performedHER2-positive (category 1). May be administered prechemotherapy andcontext of a clinical trial concurrent with radiation therapyo and with negative findings, may endocrine therapy if indicated. omit axillary lymphSee Adjuvant Endocrine Therapy (BINV-J) node staging o SeePrinciples of Radiation Therapy (BINV-I). v Chemotherapyand endocrine therapy used as adjuvant therapy should be given sequentially with endocrine therapy following chemotherapy. The benefits ofchemotherapy and of endocrine therapy are additive. However, the absolute benefit from chemotherapy may be small. The decision to add chemotherapy to endocrinetherapy should be individualized, especially in those with a favorable prognosis where the incremental benefit of chemotherapy may be smaller. Available data suggestthat sequential or concurrent endocrine therapy with radiation therapy is acceptable. ee Axillary staging may include sentinel node biopsy (category 3) or level l/ll dissection.Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version 1.2012, 01/20/12 National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN . BINV-13 25. Printed by manuel garcia on 3/13/2012 12:08:36 PM. For personal use only. Not approved for distribution. Copyright 2012 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN NCCN Guidelines Index NCCN Guidelines Version 1.2012 Breast Cancer Table of Contents Staging, DiscussionInvasive Breast Cancer LOCALLY ADVANCED INVASIVE BREAST CANCER (NON-INFLAMMATORY) CLINICAL STAGEWORKUP History and physical exam Stage IIIA CBC, plateletsT0, N2, M0 Liver function tests and alkaline phosphataseT1, N2, M0 Diagnostic bilateral mammogram, ultrasound as necessaryT2, N2, M0 Pathology review a Determination of tumor estrogen/progesterone receptor (ER/PR) status and HER2 statusbT3, N2, M0 Genetic counseling if patient is high risk for hereditary breast cancer c Stage IIIA patients Breast M RId (optional) with T3, N1, M0 disease, see BINV-1 Consider fertility counseling if indicated e See Consider systemic staging:Preoperative Chest diagnostic CT Chemotherapy Abdominal pelvic diagnostic CT or MRI (BINV-15)Stage IIIB Bone scan or fluoride PET/CT g (category 2B) T4, N0, M0 FDG PET/CT h (optional, category 2B) T4, N1, M0 T4, N2, M0Optional studies as directed by signs or symptoms: f Bone scan indicated if localized bone pain or elevated alkaline phosphataseStage lllC Abdominal pelvic diagnostic CT or MRI indicated if elevated alkaline phosphatase, Any T, N3, M0 abnormal liver function tests, abdominal symptoms, or abnormal physical examination of the abdomen or pelvis Chest diagnostic CT if pulmonary symptoms present Stage IV See Initial Workup for f Routinesystemic staging is not indicated for early breast cancer in the absence ofAny T, any N, M1Stage IV Disease (BINV-16) symptoms. g If FDG PET/CT are performed and both clearly indicate bone metastases, bonea The panel endorses the College of American Pathologists Protocol for pathology scan or fluoride PET/CT may not be needed.reporting for all invasive and non-invasive carcinomas of the breast.h FDG PET/CT can be performed at the same time as diagnostic CT. The use of PEThttp://www.cap.org.or PET/CT scanning is not indicated in the staging of clinical stage I, II, or operableb See Principles of HER2 Testing (BINV-A). III breast cancer. FDG PET/CT is most helpful in situations where standard stagingc See NCCN Genetics/Familial High-Risk Assessment: Breast and Ovarian studies are equivocal or suspicious, especially in the setting of locally advanced orGuidelines.metastatic disease. FDG PET/CT may also be helpful in identifying unsuspectedd See Principles of Dedicated Breast MRI Testing (BINV-B). regional nodal disease and/or distant metastases in LABC when used in addition toe See Fertility and Birth Control After Adjuvant Breast Cancer Treatment (BINV-C). standard staging studies.Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version 1.2012, 01/20/12 National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN . BINV-14 26. Printed by manuel garcia on 3/13/2012 12:08:36 PM. For personal use only. Not approved for distribution. Copyright 2012 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN NCCN Guidelines Index NCCN Guidelines Version 1.2012 Breast Cancer Table of Contents Staging, DiscussionInvasive Breast Cancer PREOPERATIVE CHEMOTHERAPY FORLOCOREGIONAL TREATMENT ADJUVANT TREATMENT LOCALLY ADVANCED INVASIVE BREAST CANCER (NON-INFLAMMATORY) Complete planned chemotherapy Total mastectomy + level l/ll axillary dissection + radiation therapy to chestregimen course if not completed wall and infraclavicular and preoperatively plus endocrine supraclavicular nodes (plus internal treatment if ER-positive and/or PR- mammary nodes if involved, stronglypositive (sequential chemotherapyResponse consider internal mammary nodes if not followed by endocrine therapy). clinically involved [category 2B]) Complete up to one year of delayed breast reconstruction mtrastuzumab therapy if HER2- orpositive (category 1). May be Consider lumpectomy + level l/ll axillary dissection + radiation therapy to breast administered concurrent withPreoperative and infraclavicular and supraclavicularradiation therapyo and with Seechemotherapy z,aanodes (plus internal mammary nodes ifendocrine therapy if indicated. Follow-up/ involved)Surveillance(BINV-16) Response - See above pathway Consider additional systemic No response chemotherapy and/or preoperative radiationIndividualized No responsetreatment m SeePrinciples of Breast Reconstruction Following Surgery (BINV-H). o SeePrinciples of Radiation Therapy (BINV-I). z A number of combination and single-agent chemotherapy regimens have activity in the preoperative setting. Those chemotherapy regimens recommended in the adjuvant setting (See BINV-K) may be considered in the preoperative setting. If treated with endocrine therapy, an aromatase inhibitor is preferred for postmenopausal women. aa Patients with HER2-positive tumors should be treated with preoperative chemotherapy incorporating trastuzumab for at least 9 weeks of preoperative therapy (See BINV-K).Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version 1.2012, 01/20/12 National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN . BINV-15 27. Printed by manuel garcia on 3/13/2012 12:08:36 PM. For personal use only. Not approved for distribution. Copyright 2012 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN NCCN Guidelines Index NCCN Guidelines Version 1.2012 Breast Cancer Table of Contents Staging, DiscussionInvasive Breast Cancer SURVEILLANCE/FOLLOW-UPRECURRENT WORKUP orINITIAL WORKUP FOR STAGE IV DISEASE Interval history and physical exam every 4-6mo for 5 y, then every 12 mo Annual mammography History and physical examLocoregional Women on tamoxifen: annual gynecologic CBC, platelets diseaseassessment every 12 mo if uterus present Liver function tests Women on an aromatase inhibitor or who Chest diagnostic CT Abdominal pelvic diagnostic CT or MRI gg See Treatmentexperience ovarian failure secondary to Brain MRI if suspicious CNS symptomstreatment should have monitoring of bone Bone scan or fluoride PET/CT g (category 2B) of Recurrence/health with a bone mineral density X-rays of symptomatic bones and long and Stage IV Diseasedetermination at baseline and periodicallyweight-bearing bones abnormal on bone scan (BINV-17)thereafter ff First recurrence of disease should be biopsied Assess and encourage adherence to adjuvant Determination of tumor ER/PR and HER2 statusendocrine therapy.if unknown, originally negative or not over- Evidence suggests that active lifestyle,expressed b,hhachieving and maintaining an ideal body Genetic counseling if patient is high risk for Systemicweight (20-25 BMI) may lead to optimal breast hereditary breast cancer c diseasecancer outcomes.b See Principles of HER2 Testing (BINV-A).c SeeNCCN Genetics/Familial High-Risk Assessment: Breast and Ovarian Guidelines.g If FDG PET/CT are performed and both clearly indicate bone metastases, bone scan or fluoride PET/CT may not be needed.ff The use of estrogen, progesterone, or selective estrogen receptor modulators to treat osteoporosis or osteopenia in women with breast cancer is discouraged. The use of a bisphosphonate is generally the preferred intervention to improve bone mineral density. Optimal duration of bisphosphonate therapy has not been established. Factors to consider for duration of anti-osteoporosis therapy include bone mineral density, response to therapy, and risk factors for continued bone loss or fracture. Women treated with a bisphosphonate should undergo a dental examination with preventive dentistry prior to the initiation of therapy, and should take supplemental calcium and vitamin D.gg The use of PET or PET/CT scanning should generally be discouraged for the evaluation of metastatic disease except in those clinical situations where other staging studies are equivocal or suspicious. Even in these situations, biopsy of equivocal or suspicious sites is more likely to provide useful information.hh False-negative ER and/or PR determinations occur, and there may be discordance between the ER and/or PR determination between the primary and metastatic tumor(s). Therefore, endocrine therapy with its low attendant toxicity may be considered in patients with non-visceral or asymptomatic visceral tumors, especially in patients with clinical characteristics predicting for a hormone receptor-positive tumor (eg, long disease-free interval, limited sites of recurrence, indolent disease, older age).Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version 1.2012, 01/20/12 National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN . BINV-16 28. Printed by manuel garcia on 3/13/2012 12:08:36 PM. For personal use only. Not approved for distribution. Copyright 2012 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN NCCN Guidelines Index NCCN Guidelines Version 1.2012 Breast Cancer Table of Contents Staging, DiscussionInvasive Breast Cancer SYSTEMIC TREATMENT OF RECURRENT OR STAGE IV DISEASE Initial treatment with lumpectomy Total mastectomy + axillary lymph node staging if + radiation therapy level l/ll axillary dissection not previously done kkLocal only Initial treatment with mastectomy + level l / llrecurrence Surgical resection if possible ll axillary dissection and prior radiation therapy Initial treatment with mastectomy Surgical resection if possible + radiation therapy to no prior radiation therapychest wall and supraclavicular and infraclavicular nodes Consider Surgical resection if possible + radiation therapy if systemicRegional Axillary recurrence possible to chest wall, supraclavicular and therapyonly infraclavicular nodes, and axillaor Radiation therapy if possible to chest wall andLocal andSupraclavicular recurrence supraclavicular and infraclavicular nodesregionalrecurrence Radiation therapy if possible to chest wall, Internal mammary node recurrencesupraclavicular and infraclavicular nodes, and internal mammary nodesAdd denosumab, ER and/or PR positive; HER2 negative b Bone disease present zoledronic acid, or See BINV-18pamidronate ii ER and/or PR positive; HER2 positive b SystemicER and PR negative, or ER and/or PR positive disease ii,jj and endocrine refractory; HER2 negative bSee BINV-19 Bone disease not presentER/PR negative or ER and/or PR positiveSee BINV-20 and endocrine refractory; HER2 positivebb See Principles of HER2 Testing (BINV-A).ii Denosumab, zoledronic acid, or pamidronate (all with calcium and vitamin D supplementation) should be givenSurgery, radiation, or regional chemotherapy (e.g., intrathecal(category 1) in addition to chemotherapy or endocrine therapy if bone metastasis is present, expected survival is 3methotrexate) indicated for localized clinical scenarios: months, and renal function is adequate. Patients should undergo a dental examination with preventive dentistry prior to initiation of this therapy. The optimal schedule and duration of denosumab, zoledronic acid, or pamidronate are1. Brain metastases8. Impending pathologic fractureunknown.2. Leptomeningeal disease9. Pathologic fracture jj See NCCN Palliative Care Guidelines.3. Choroid metastases 10. Cord compression4. Pleural effusion 11. Localized painful bone or kk In women with a local breast recurrence after breast-conserving surgery who had a prior sentinel lymph node5. Pericardial effusion soft-tissue disease6. Biliary obstruction12. Chest wall disease biopsy, a repeat SNB may be technically possible. The accuracy of repeat SNB is unproven, and the prognostic7. Ureteral obstruction hyperthermia (category 3)significance of repeat SNB after mastectomy is unknown and its use is discouraged.if radiation therapy used llIf not technically resectable, consider systemic therapy to best response, then resect if possible.Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version 1.2012, 01/20/12 National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN . BINV-17 29. Printed by manuel garcia on 3/13/2012 12:08:36 PM. For personal use only. Not approved for distribution. Copyright 2012 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN NCCN Guidelines Index NCCN Guidelines Version 1.2012 Breast Cancer Table of Contents Staging, DiscussionInvasive Breast Cancer SYSTEMIC TREATMENT OF RECURRENT OR STAGE IV DISEASE ER and/or PR POSITIVE; HER2 NEGATIVE OR POSITIVE Ovarian ablation or suppression, Premenopausal ccplus endocrine therapy as for postmenopausal women nn,oo Prior endocrine therapy within 1y Postmenopausal cc Visceral crisis Consider initial chemotherapy pp (See BINV-19 and BINV-20)See Follow-upER and/or PR positive;Therapy ForHER2 negative bOvarian ablation or suppression, Endocrine plus endocrine therapy as forTreatment ofER and/or PR positive; postmenopausal women nn,oo Recurrence / Stage Premenopausal ccor IV Disease (BINV-21)HER2 positive b Selective estrogen receptor modulators oo Aromatase inhibitor oo,qq No prior endocrineorPostmenopausal cc,mm therapy within 1y Selective estrogen receptor modulators or selective estrogen receptor down-regulator oo b See Visceral crisis Consider initial chemotherapy pp Principles of HER2 Testing (BINV-A). cc Definition of Menopause (BINV-L).(See BINV-19 and BINV-20) mm Limited studies document a progression-free survival advantage of adding trastuzumab or lapatinib to aromatase inhibition in postmenopausal patients with qq A single study (S0226) in women with hormone receptor-positive breast cancer and ER-positive, HER2-positive disease. However, no overall survival advantage has no prior chemotherapy, biological therapy, or endocrine therapy for metastatic been demonstrated. disease demonstrated that the addition of fulvestrant to anastrozole resulted in nn See Subsequent Endocrine Therapy (BINV-N).prolongation of time to progression (Hazard rate for recurrence 0.80; 95% CI 0.68 - oo It is unclear that women presenting at time of initial diagnosis with metastatic0.94; stratified log-rank p=0.007) and improvement in overall survival (hazard rate disease will benefit from the performance of palliative local breast surgery and/or 0.81; 95% CI 0.65 - 1.00; stratified log-rank p = 0.049). Subset analysis suggested radiation therapy. Generally this palliative local therapy should be considered only that patients without prior adjuvant tamoxifen and more than 10 years since after response to initial systemic therapy.diagnosis experienced the greatest benefit. A study of similar design (FACT) pp See Preferred Chemotherapy Regimens for Recurrent or Metastatic Breastdemonstrated no advantage in time to progression with the addition of fulvestrant to Cancer (BINV-O). anastrozole (Hazard rate 0.99; 95% CI 0.81-1.20; p=0.91).Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version 1.2012, 01/20/12 National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN . BINV-18 30. Printed by manuel garcia on 3/13/2012 12:08:36 PM. For personal use only. Not approved for distribution. Copyright 2012 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN NCCN Guidelines Index NCCN Guidelines Version 1.2012 Breast Cancer Table of Contents Staging, DiscussionInvasive Breast Cancer SYSTEMIC TREATMENT OF RECURRENT OR STAGE IV DISEASE ER and PR NEGATIVE; or ER and/or PR POSITIVE and ENDOCRINE REFRACTORY; HER2 NEGATIVEConsider additional trialSee Endocrineof endocrine therapy, ifTherapy (BINV-18) Yesnot endocrineER and PRnegative; or ER Bone or softrefractory hh,nn,rr No response to 3and/or PR tissue only orsequential regimens Consider no furtherorChemotherapy pp,rrorcytotoxic therapy; transitionpositive andAsymptomaticECOG performanceto palliative care jjendocrinevisceralstatus 3refractory; andNoChemotherapy pp,rrHER2 negative bb SeePrinciples of HER2 Testing (BINV-A).hh False-negative ER and/or PR determinations occur, and there may be discordance between the ER and/or PR determination between the primary and metastatic tumor(s). Therefore, endocrine therapy with its low attendant toxicity may be considered in patients with non-visceral or asymptomatic visceral tumors, especially in patients with clinical characteristics predicting for a hormone receptor-positive tumor (eg, long disease-free interval, limited sites of recurrence, indolent disease, older age).jj See NCCN Palliative Care Guidelines.nn See Subsequent Endocrine Therapy for Systemic Disease (BINV-N).pp See Preferred Chemotherapy Regimens for Recurrent or Metastatic Breast Cancer (BINV-O).rr See Principles of Monitoring Metastatic Disease (BINV-M).Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version 1.2012, 01/20/12 National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN . BINV-19 31. Printed by manuel garcia on 3/13/2012 12:08:36 PM. For personal use only. Not approved for distribution. Copyright 2012 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN NCCN Guidelines Index NCCN Guidelines Version 1.2012 Breast Cancer Table of Contents Staging, DiscussionInvasive Breast Cancer SYSTEMIC TREATMENT OF RECURRENT OR STAGE IV DISEASE ER and PR NEGATIVE; or ER and/or PR POSITIVE and ENDOCRINE REFRACTORY; and HER2 POSITIVEConsider trial ofendocrine therapy, if notendocrineSee Endocrine Therapy (BINV-18)refractoryhh,nn,rr ER and PRYes negative; or ERBone or soft and/or PRtissue only positive and or Continue HER2No response endocrineAsymptomatic targeted therapy, Consider noto 3 sequential refractory; andvisceral typically infurther cytotoxicTrastuzumab regimens HER2 positive b Nocombination with or therapy;chemotherapy pp,rr,ss,tt other chemotherapy,ECOG transition to or trastuzumab + performancepalliative care jj lapatinibstatus 3 b See Principles of HER2 Testing (BINV-A). hh False-negativeER and/or PR determinations occur, and there may be discordance between the ER and/or PR determination between the primary and metastatictumor(s). Therefore, endocrine therapy with its low attendant toxicity may be considered in patients with non-visceral or asymptomatic visceral tumors, especially inpatients with clinical characteristics predicting for a hormone receptor-positive tumor (eg, long disease-free interval, limited sites of recurrence, indolent disease, olderage). jj See NCCN Palliative Care Guidelines. nn See Subsequent Endocrine Therapy for Systemic Disease (BINV-N). pp See Preferred Chemotherapy Regimens for Recurrent or Metastatic Breast Cancer (BINV-O). rr See Principles of Monitoring Metastatic Disease (BINV-M). ss Continued trastuzumab following progression on first line-trastuzumab containing chemotherapy for metastatic breast cancer. The optimal duration of trastuzumab inpatients with long-term control of disease is unknown. tt Trastuzumab given in combination with an anthracycline is associated with significant cardiac toxicity.Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version 1.2012, 01/20/12 National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN . BINV-20 32. Printed by manuel garcia on 3/13/2012 12:08:36 PM. For personal use only. Not approved for distribution. Copyright 2012 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN NCCN Guidelines Index NCCN Guidelines Version 1.2012 Breast Cancer Table of Contents Staging, DiscussionInvasive Breast Cancer FOLLOW-UP THERAPY FOR ENDOCRINE TREATMENT OF RECURRENT OR STAGE IV DISEASENo clinical benefit after 3 YesChemotherapy ppContinue endocrineconsecutive endocrine(As in BINV-17)therapy until therapy regimensprogression or Progressionrrorunacceptable toxicity Symptomatic visceral Trial of newdisease No endocrine therapy nn nn SeeSubsequent Endocrine Therapy for Systemic Disease (BINV-N). pp SeePreferred Chemotherapy Regimens for Recurrent or Metastatic Breast Cancer (BINV-O). rr See Principles of Monitoring Metastatic Disease (BINV-M).Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version 1.2012, 01/20/12 National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN . BINV-21 33. Printed by manuel garcia on 3/13/2012 12:08:36 PM. For personal use only. Not approved for distribution. Copyright 2012 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN NCCN Guidelines Index NCCN Guidelines Version 1.2012 Breast Cancer Table of Contents Staging, DiscussionInvasive Breast Cancer PRINCIPLES OF HER2 TESTING 1,2Laboratory meetsNo Send sample to reference laboratory Initial testingquality assuranceIHC 0,1+ HER2 (-) by IHC 3 standards for IHCHER2 testingmethodology IHCBorderlineYes IHC 2+ ISH testingtestingresult 4IHC 3+ HER2 (+)No Send sample to reference laboratoryLaboratory meets Initial testingquality assurance ISH (-)HER2 (-) by ISH 3 standards for ISH IHC testingHER2 testingmethodology ISH BorderlineHER2 (-)Yes result 5 ISH retesttesting Borderline result Count (See Discussion additional cellssection)ISH+ HER2 (+) 1 Seealso, Carlson RW, Moench SJ, Hammond, MEH, et al. HER2 testing in breast cancer: NCCN task force report and recommendations. JNCCN 4:S-1-S-24, 2006. 2 HER2 testing should be done only in laboratories accredited to perform such testing. Ongoing proficiency testing and full reporting of HER2 assay methods and results are required. A laboratory may perform only those tests have been demonstrated to conform to these quality assurance standards. All other HER2 testing should be sent to a qualified reference laboratory. 3 Either an immunohistochemistry (IHC) assay or a in situ hybridization (ISH) assay can be used to make an initial assessment of HER2 tumor status. All HER2 assays, whether FDA-approved or not, must be validated. Validation of a HER2 test is defined as at least 95% concordance when the testing method performed in a laboratory is compared with one of the following: a validated HER2 testing method performed in the same laboratory; a validated HER2 testing method performed in another laboratory; or validated reference lab results. Borderline samples should not be included in the validation study. These algorithms are based on the assumption that all validated HER2 tests have been shown to be at least 95% concordant with the complementary form of the HER2 test, either by direct testing or association with the levels of concordance between complementary testing achieved by the validating laboratory. 4 Borderline IHC samples (eg, IHC 2+) are subjected to reflex testing by a validated complementary (eg, in situ hybridization [ISH]) method that has shown at least 95% concordance between IHC 0, 1+ results and ISH non-amplified results, and IHC 3+ results and ISH amplified results. 5 Borderline in situ hybridization (ISH) samples (eg, an average HER2 gene/chromosome 17 ratio of 1.8-2.2 or an average HER2 gene copy number of > 4 - < 6) should undergo: counting of additional cells; retesting by ISH; or reflex testing by a validated IHC method is at least 95% concordant with ISH as described above.Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version 1.2012, 01/20/12 National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN . BINV-A 34. Printed by manuel garcia on 3/13/2012 12:08:36 PM. For personal use only. Not approved for distribution. Copyright 2012 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN NCCN Guidelines Index NCCN Guidelines Version 1.2012 Breast Cancer Table of Contents Staging, DiscussionInvasive Breast Cancer PRINCIPLES OF DEDICATED BREAST MRI TESTINGSee NCCN Breast Screening and Diagnosis Guidelines for indications for screening MRI in women at increased breast cancer risk.Personnel, facility and equipment Breast MRI examinations should be performed and interpreted by an expert breast imaging team working in concert with themultidisciplinary treatment team. Breast MRI examinations require a dedicated breast coil and breast imaging radiologists familiar with the optimal timing sequences andother technical details for image interpretation. The imaging center should have the ability to perform MRI guided needle samplingand/or wire localization of MRI detected findings.Clinical indications and applications May be used for staging evaluation to define extent of cancer or presence of multifocal or multicentric cancer in the ipsilateral breast, oras screening of the contralateral breast cancer at time of initial diagnosis (category 2B). There are no data that demonstrate that use ofMRI to affect choice of local therapy improves outcome (local recurrence or survival). May be helpful for breast cancer evaluation before and after neoadjuvant therapy to define extent of disease, response to treatment, andpotential for breast conserving therapy. May be useful to detect additional disease in women with mammographically dense breast, but available data do not show differentialdetection rates by any subset by breast pattern (breast density) or disease type (eg. DCIS, invasive ductal cancer, invasive lobularcancer) May be useful for identifying primary cancer in women with axillary nodal adenocarcinoma or with Pagets disease of the nipple withbreast primary not identified on mammography, ultrasound, or physical examination Falsely positive findings on breast MRI are common. Surgical decisions should not be based solely on the MRI findings. Additionaltissue sampling of areas of concern identified by breast MRI is recommended. The utility of MRI in follow-up screening of women with prior breast cancer is undefined. It should generally be considered only in thosewhose lifetime risk of a second primary breast cancer is greater than 20% based on models largely dependent on family history, such asin those with the risk associated with inherited susceptibility to breast cancer. Houssami N, Ciatto S, Macaskill P, Lord SJ, Warren RM, Dixon JM, Irwig L. Accuracy and surgical impact of magnetic resonance imaging in breast cancer staging: systematic review and meta-analysis in detection of multifocal and multicentric cancer. J Clin Oncol 2008;26:3248-3258.Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version 1.2012, 01/20/12 National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN . BINV-B 35. Printed by manuel garcia on 3/13/2012 12:08:36 PM. For personal use only. Not approved for distribution. Copyright 2012 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN NCCN Guidelines Index NCCN Guidelines Version 1.2012 Breast Cancer Table of Contents Staging, DiscussionInvasive Breast Cancer FERTILITY AND BIRTH CONTROL AFTER ADJUVANT BREAST CANCER TREATMENT All premenopausal patients should be informed about the potential impact of chemotherapy on fertility and asked about their desire for potential future pregnancies. Patients who may desire future pregnancies should be referred to fertility specialists before chemotherapy Although amenorrhea frequently occurs during or after chemotherapy it appears the majority of women younger than 35 y resume menses within 2 y of finishing adjuvant chemotherapy Menses and fertility are not necessarily linked. Absence of regular menses, particularly if the patient is taking tamoxifen does not necessarily imply lack of fertility. Conversely, the presence of menses does not guarantee fertility. There is limited data regarding continued fertility after chemotherapy Patients should not become pregnant during treatment with radiation therapy, chemotherapy, or endocrine therapy. Although data are limited, hormone-based birth control is discouraged regardless of the hormone receptor status of the patients cancer Alternative methods of birth control include intrauterine devices (IUD), barrier methods or for patients with no intent for future pregnancies, tubal ligation or vasectomy for the partner. No therapy has been shown to preserve fertility in patients receiving chemotherapy Breast feeding following breast conserving cancer treatment is not contraindicated. However the quantity and quality of breast milk produced by the breast conserved may not be sufficient or may be lacking some of the nutrients needed. Breast feeding during active treatment with chemotherapy and endocrine therapy is not recommended.Note: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version 1.2012, 01/20/12 National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN . BINV-C 36. Printed by manuel garcia on 3/13/2012 12:08:36 PM. For personal use only. Not approved for distribution. Copyright 2012 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN NCCN Guidelines Index NCCN Guidelines Version 1.2012 Breast Cancer Table of Contents Staging, Discussion SURGICAL AXILLARY STAGING - STAGE I, IIA, IIB and lllA T3, N1, M0FNA or coreAxillary dissection level I/IIbiopsy positive Clinically node positive at time of diagnosis1FNA or corebiopsy negativeClinicalSentinel node Consider no further surgeryStage I, IIA, negative6 (category 1)IIB and lllAT3, N1, M0 Meets ALL of the following criteria:Yes to all T1 or T2 tumor Clinically node Sentinel nodeSentinel node 1 or 2 positive SLNs negative at timemapping andpositive6 excision 2,3,4,5 Breast conserving therapy of diagnosis Whole breast RT plannedNo No neoadjuvant chemotherapySentinel nodenot identifiedAxillary dissection level I/II 1Consider pathologic confirmation of malignancy in clinically positive nodes using ultrasound-guided FNA or core biopsy in determining if a patient needs axillary lymph node dissection. 2A sentinel node team must have documented experience with sentinel node biopsy in breast cancer. The team includes surgeon, radiologists, nuclear medicine physician, pathologist, and prior discussion with medical and radiation oncologists on use of sentinel node for treatment decisions. 3Axillary sentinel node biopsy in all cases; internal mammary sentinel node biopsy is optional if drainage maps to internal mammary nodes (category 3). 4Sentinel lymph node mapping injections may be peritumoral, subareolar, or subdermal. However, only peritumoral injections map to the internal mammary lymph node(s). 5 Results of randomized clinical trials indicate that there is a lower risk of mobidity associated with sentinel node mapping and excision than with level l/ll axillary dissection. 6Sentinel node involvement is defined by multilevel node sectioning with hematoxylin and eosin (H&E) staining. Cytokeratin Immunohistochemistry (IHC) may be used for equivocal cases on H&E. Routine cytokeratin IHC to define node involvement is not recommended in clinical decision making.Return to LocoregionalNote: All recommendations are category 2A unless otherwise indicated.Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.Treatment (BINV-2) Version 1.2012, 01/20/12 National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN .BINV-D 37. Printed by manuel garcia on 3/13/2012 12:08:36 PM. For personal use only. Not approved for distribution. Copyright 2012 National Comprehensive Cancer Network, Inc., All Rights Reserved. NCCN NCCN Guidelines Index NCCN Guidelines Version 1.2012 Breast Cancer Table of Contents Staging, DiscussionInvasive Breast Cancer AXILLARY LYMPH NODE STAGINGIn the absence of definitive data demonstrating superior survival from the performance of axillary lymph node dissection, patients who haveparticularly favorable tumors, patients for whom the selection of adjuvant systemic therapy is unlikely to be affected, for the elderly, or thosewith serious comorbid conditions, the performance of axillary lymph node dissection may be considered optional. The axillary dissectionshould be extended to include level lll nodes only if there